HNF1 homeobox A (hepatocyte nuclear factor 1 homeobox A), also known asHNF1A, is a humangene onchromosome 12.[5][6][7] It is ubiquitously expressed in many tissues and cell types.[8] Theprotein encoded by this gene is atranscription factor that is highly expressed in the liver and is involved in the regulation of theexpression of several liver-specific genes.[9]Mutations in theHNF1A gene have been known to causediabetes.[10] TheHNF1A gene also contains aSNP associated with increased risk ofcoronary artery disease.[11]
This protein belongs to the HNF1homeobox family.[13] It contains 3 functional domains: anN-terminaldimerization domain (residues 1–32), a bipartite DNA-binding motif containing an atypicalPOU-homeodomain (residues 98–280), and aC-terminaltransactivation domain (residues 281–631).[14][15] There is also a flexible linker (residues 33–97) which connects the dimerization andDNA binding domains.[15] Crystal structures have been solved for the dimerization domain, which forms afour-helix bundle where twoα helices are separated by a turn; the DNA-binding motif, which forms ahelix-turn-helix structure; and the POU-homeodomain, which is composed of three α helices, contained in the motif. Thishomeodomain is considered atypical due to an extended loop inserted between the second and third helices relative to the canonical homeodomain fold. The atypical insertion is thought to stabilize the interface to improvetranscriptional efficiency.[14] Meanwhile, the dimerization domain is responsible for the homo- andheterodimerization of HNF-1α. The resulting dimer contains a rigid "mini-zipper", comprising α-helices 1 and 1′, linked by a non-canonical tight turn to a flexible C-terminal comprising α-helices 2 and 2′.[15]
In humans, mutations in HNF1A cause diabetes that responds to low dosesulfonylurea agents.[31] The identification of extreme sulfonylurea sensitivity in patients with diabetes mellitus owing to heterozygous mutations in HNF1A presents a clear example of the relevance of HNF1A in diabetes patients and howpharmacogenetics can contribute in patient care.[32] For example, patients with maturity onset diabetes of the young owing to mutations in HNF1A (which accounts for ~3% of all diabetes mellitus cases diagnosed under the age of 30 years) are extremely sensitive to sulfonylurea treatment and can successfully transition off insulin treatment.[10] Likewise, patients with diabetes caused by mutations in the HNF1A gene have been described as sensitive to thehypoglycemic effects of sulphonylureas. The cause of hyperglycemia appears to alter the response to hypoglycemic drugs. Accordingly, HNF-1α-induced diabetes has marked sulphonylurea sensitivity. This pharmacogenetic effect is consistent with models of HNF-1α deficiency, and the genetic basis of hyperglycemia may have implications for patient management.[10] Commongenetic variation within HNF1A is also associated with risk of developingtype 2 diabetes and increasedpenetrance of early-onset diabetes[33]
A multi-locus genetic risk score study based on a combination of 27 loci, including the HNF1A gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[11]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Szpirer C, Riviere M, Cortese R, Nakamura T, Islam MQ, Levan G, et al. (June 1992). "Chromosomal localization in man and rat of the genes encoding the liver-enriched transcription factors C/EBP, DBP, and HNF1/LFB-1 (CEBP, DBP, and transcription factor 1, TCF1, respectively) and of the hepatocyte growth factor/scatter factor gene (HGF)".Genomics.13 (2):293–300.doi:10.1016/0888-7543(92)90245-N.PMID1535333.
^abVaxillaire M, Boccio V, Philippi A, Vigouroux C, Terwilliger J, Passa P, et al. (April 1995). "A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q".Nature Genetics.9 (4):418–23.doi:10.1038/ng0495-418.PMID7795649.S2CID665243.
^Courtois G, Morgan JG, Campbell LA, Fourel G, Crabtree GR (October 1987). "Interaction of a liver-specific nuclear factor with the fibrinogen and alpha 1-antitrypsin promoters".Science.238 (4827):688–92.Bibcode:1987Sci...238..688C.doi:10.1126/science.3499668.PMID3499668.
^abcPearson ER, Starkey BJ, Powell RJ, Gribble FM, Clark PM, Hattersley AT (October 2003). "Genetic cause of hyperglycaemia and response to treatment in diabetes".Lancet.362 (9392):1275–81.doi:10.1016/S0140-6736(03)14571-0.PMID14575972.S2CID34914098.
^abcNarayana N, Phillips NB, Hua QX, Jia W, Weiss MA (September 2006). "Diabetes mellitus due to misfolding of a beta-cell transcription factor: stereospecific frustration of a Schellman motif in HNF-1alpha".Journal of Molecular Biology.362 (3):414–29.doi:10.1016/j.jmb.2006.06.086.PMID16930618.
^Gu N, Adachi T, Matsunaga T, Takeda J, Tsujimoto G, Ishihara A, et al. (August 2006). "Mutant HNF-1alpha and mutant HNF-1beta identified in MODY3 and MODY5 downregulate DPP-IV gene expression in Caco-2 cells".Biochemical and Biophysical Research Communications.346 (3):1016–23.doi:10.1016/j.bbrc.2006.06.010.PMID16781669.
^Gu N, Tsuda M, Matsunaga T, Adachi T, Yasuda K, Ishihara A, et al. (December 2008). "Glucose regulation of dipeptidyl peptidase IV gene expression is mediated by hepatocyte nuclear factor-1alpha in epithelial intestinal cells".Clinical and Experimental Pharmacology & Physiology.35 (12):1433–9.doi:10.1111/j.1440-1681.2008.05015.x.PMID18671716.S2CID24464350.
^Shih DQ, Bussen M, Sehayek E, Ananthanarayanan M, Shneider BL, Suchy FJ, et al. (April 2001). "Hepatocyte nuclear factor-1alpha is an essential regulator of bile acid and plasma cholesterol metabolism".Nature Genetics.27 (4):375–82.doi:10.1038/86871.PMID11279518.S2CID22640762.
^Bluteau O, Jeannot E, Bioulac-Sage P, Marqués JM, Blanc JF, Bui H, et al. (October 2002). "Bi-allelic inactivation of TCF1 in hepatic adenomas".Nature Genetics.32 (2):312–5.doi:10.1038/ng1001.PMID12355088.S2CID11919671.
^Köbel M, Kalloger SE, Carrick J, Huntsman D, Asad H, Oliva E, et al. (January 2009). "A limited panel of immunomarkers can reliably distinguish between clear cell and high-grade serous carcinoma of the ovary".The American Journal of Surgical Pathology.33 (1):14–21.doi:10.1097/PAS.0b013e3181788546.PMID18830127.S2CID19610205.
^Offman SL, Longacre TA (September 2012). "Clear cell carcinoma of the female genital tract (not everything is as clear as it seems)".Advances in Anatomic Pathology.19 (5):296–312.doi:10.1097/PAP.0b013e31826663b1.PMID22885379.S2CID33159622.
^Owen KR (June 2016). "Treating young adults with type 2 diabetes or monogenic diabetes".Best Practice & Research. Clinical Endocrinology & Metabolism.30 (3):455–67.doi:10.1016/j.beem.2016.05.002.PMID27432078.
Eastman Q, Grosschedl R (April 1999). "Regulation of LEF-1/TCF transcription factors by Wnt and other signals".Current Opinion in Cell Biology.11 (2):233–40.doi:10.1016/S0955-0674(99)80031-3.PMID10209158.
